This project will extend our previous studies on modulation of lymphocyte function by histamine, which have established that: (1) Histamine inhibits the activity of mouse cytotoxic T lymphocytes (CTL) by interacting with specific histamine-type 2 (hist-2) receptors, resulting in activation of adenylate cyclase and an increase in intracellular cAMP levels. (2) Effector lymphocyte populations vary widely in responsiveness to histamine and to several other cAMP-active agents, probably because these populations differ in several biochemical pathways, including receptor numbers, receptor-adenylate cyclase coupling, and post-cAMP steps. (3) The local environment interacts with CTL to determine the level of cAMP responsiveness. (4) Histamine is a weak inhibitor of CTL generation from mouse spleen lymphocytes. (5) Histamine is a potent inhibitor of human mitogen-induced lymphocyte proliferation. We propose that histamine is an endogenous modulator of lymphocyte differentiation and effector function. As such, it acts selectively on distinct lymphocyte subpopulations, on defined phases of the immune response, and perhaps in certain individuals. To evaluate this hypothesis, the project's aims are to analyze, quantitatively, changes during the immune response in sensitivity of CTL from different lymphoid sites to inhibition by distinct cAMP-active agents; to define, by cell transfer experiments, the roles of the local environment, vs. factors intrinsic to the CTL themselves, in determining CTL cAMP responsiveness; to measure parameters of biochemical pathways of cAMP metabolism in different lymphocyte subpopulations, and in CTL clones; to define the effects of histamine and other cyclic AMP-active agents on generation of mouse CTL and on generation of human CTL, by testing their action at distinct stages of the process of CTL differentiation; to identify any differences among mouse strains or individual humans in responsiveness to cAMP-active agonists; and to analyze the physiologic role of histamine in modulating the immune response in vivo, by assessing the response in mast cell-deficient mice and mice treated with antihistamines or histidine decarboxylase inhibitors.